scholarly journals Dalbavancin binds ACE2 to block its interaction with SARS-CoV-2 spike protein and is effective in inhibiting SARS-CoV-2 infection in animal models

Cell Research ◽  
2020 ◽  
Vol 31 (1) ◽  
pp. 17-24 ◽  
Author(s):  
Gan Wang ◽  
Meng-Li Yang ◽  
Zi-Lei Duan ◽  
Feng-Liang Liu ◽  
Lin Jin ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Spike Protein ◽  
Drug Candidate ◽  
Peptide Drug ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
High Affinity ◽  
Plasma Half Life

AbstractInfection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic worldwide. Currently, however, no effective drug or vaccine is available to treat or prevent the resulting coronavirus disease 2019 (COVID-19). Here, we report our discovery of a promising anti-COVID-19 drug candidate, the lipoglycopeptide antibiotic dalbavancin, based on virtual screening of the FDA-approved peptide drug library combined with in vitro and in vivo functional antiviral assays. Our results showed that dalbavancin directly binds to human angiotensin-converting enzyme 2 (ACE2) with high affinity, thereby blocking its interaction with the SARS-CoV-2 spike protein. Furthermore, dalbavancin effectively prevents SARS-CoV-2 replication in Vero E6 cells with an EC50 of ~12 nM. In both mouse and rhesus macaque models, viral replication and histopathological injuries caused by SARS-CoV-2 infection are significantly inhibited by dalbavancin administration. Given its high safety and long plasma half-life (8–10 days) shown in previous clinical trials, our data indicate that dalbavancin is a promising anti-COVID-19 drug candidate.

scholarly journals Engineering human ACE2 to optimize binding to the spike protein of SARS coronavirus 2

Science ◽  
2020 ◽  
Vol 369 (6508) ◽  
pp. 1261-1265 ◽  
Author(s):  
Kui K. Chan ◽  
Danielle Dorosky ◽  
Preeti Sharma ◽  
Shawn A. Abbasi ◽  
John M. Dye ◽  
...  
Keyword(s):  
Host Cells ◽  
Viral Escape ◽  
Spike Protein ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
High Affinity ◽  
Decoy Receptors ◽  
Catalytically Active ◽  
Interaction Surface

The spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds angiotensin-converting enzyme 2 (ACE2) on host cells to initiate entry, and soluble ACE2 is a therapeutic candidate that neutralizes infection by acting as a decoy. By using deep mutagenesis, mutations in ACE2 that increase S binding are found across the interaction surface, in the asparagine 90–glycosylation motif and at buried sites. The mutational landscape provides a blueprint for understanding the specificity of the interaction between ACE2 and S and for engineering high-affinity decoy receptors. Combining mutations gives ACE2 variants with affinities that rival those of monoclonal antibodies. A stable dimeric variant shows potent SARS-CoV-2 and -1 neutralization in vitro. The engineered receptor is catalytically active, and its close similarity with the native receptor may limit the potential for viral escape.

scholarly journals Targeting Virus-Host Interaction: An in Silico Approach to Develop Promising Inhibitors Against COVID-19

2020 ◽  
Author(s):  
Jitendra Subhash Rane ◽  
Aroni Chatterjee ◽  
Rajni Khan ◽  
Abhijeet Kumar ◽  
Shashikant Ray
Keyword(s):  
Angiotensin Converting Enzyme ◽  
In Silico ◽  
Virus Disease ◽  
Spike Protein ◽  
Converting Enzyme ◽  
Host Cell Membrane ◽  
Angiotensin Converting Enzyme 2 ◽  
Host Interaction

The entire human population all over the globe is currently facing appalling conditions due to<br>the spread of infection from COVID-19 (corona virus disease-2019). In the last few months<br>enormous amount of studies have been continuously trying to target several potential drug<br>sites to identify a novel therapeutic target. Spike protein of severe acute respiratory syndrome<br>coronavirus 2 (SARS-CoV-2) is also being targeted by several scientific groups as a novel<br>drug target. The spike glycoprotein protein is present on the surface of the virion and binds to<br>the human angiotensin-converting enzyme-2 (hACE2) membrane receptor thereby promoting<br>its fusion to the host cell membrane. The binding and internalization of the virus is a crucial<br>step in the process of infection and hence any molecule that can inhibit this, certainly holds a<br>significant therapeutic value. We have identified AP-NP (2-(2-amino-5-(naphthalen-2-<br>yl)pyrimidin-4-yl)phenol) and AP-4-Me-Ph (2-(2-amino-5-(p-tolyl)pyrimidin-4-yl)phenol)<br>from a group of diaryl pyrimidine derivatives which appear to bind at the interface of<br>hACE2-SARS-CoV-2S complex (human angiotensin converting enzyme 2 and spike<br>glycoprotein complex) with a low binding energy (<-8 Kcal/mol). In this in-silico study we<br>also found that AP-NP interacts with S1 domain of C-terminal part of SARS-CoV-2S<br>however AP-4-Me-Ph was found to interact with S2 domain of SARS-CoV-2S. The result<br>suggested that AP-NP and AP-4-Me-Ph have potential to inhibit the interaction between<br>spike protein and hACE2 receptor also AP-4-Me-Ph might be prevent internalization of the<br>virion within the host. Further in vitro and in vivo study will strengthen these drug candidates<br>against the COVID-19. <br>

scholarly journals Targeting Virus-Host Interaction: An in Silico Approach to Develop Promising Inhibitors Against COVID-19

2020 ◽  
Author(s):  
Jitendra Subhash Rane ◽  
Aroni Chatterjee ◽  
Rajni Khan ◽  
Abhijeet Kumar ◽  
Shashikant Ray
Keyword(s):  
Angiotensin Converting Enzyme ◽  
In Silico ◽  
Virus Disease ◽  
Spike Protein ◽  
Converting Enzyme ◽  
Host Cell Membrane ◽  
Angiotensin Converting Enzyme 2 ◽  
Host Interaction

The entire human population all over the globe is currently facing appalling conditions due to<br>the spread of infection from COVID-19 (corona virus disease-2019). In the last few months<br>enormous amount of studies have been continuously trying to target several potential drug<br>sites to identify a novel therapeutic target. Spike protein of severe acute respiratory syndrome<br>coronavirus 2 (SARS-CoV-2) is also being targeted by several scientific groups as a novel<br>drug target. The spike glycoprotein protein is present on the surface of the virion and binds to<br>the human angiotensin-converting enzyme-2 (hACE2) membrane receptor thereby promoting<br>its fusion to the host cell membrane. The binding and internalization of the virus is a crucial<br>step in the process of infection and hence any molecule that can inhibit this, certainly holds a<br>significant therapeutic value. We have identified AP-NP (2-(2-amino-5-(naphthalen-2-<br>yl)pyrimidin-4-yl)phenol) and AP-4-Me-Ph (2-(2-amino-5-(p-tolyl)pyrimidin-4-yl)phenol)<br>from a group of diaryl pyrimidine derivatives which appear to bind at the interface of<br>hACE2-SARS-CoV-2S complex (human angiotensin converting enzyme 2 and spike<br>glycoprotein complex) with a low binding energy (<-8 Kcal/mol). In this in-silico study we<br>also found that AP-NP interacts with S1 domain of C-terminal part of SARS-CoV-2S<br>however AP-4-Me-Ph was found to interact with S2 domain of SARS-CoV-2S. The result<br>suggested that AP-NP and AP-4-Me-Ph have potential to inhibit the interaction between<br>spike protein and hACE2 receptor also AP-4-Me-Ph might be prevent internalization of the<br>virion within the host. Further in vitro and in vivo study will strengthen these drug candidates<br>against the COVID-19. <br>

scholarly journals Virtual screening as therapeutic strategy of COVID-19 targeting angiotensin-converting enzyme 2

2021 ◽  
Vol 2 (1) ◽  
pp. 16-27
Author(s):  
Zahra Sharifinia ◽  
◽  
Samira Asadi ◽  
Mahyar Irani ◽  
Abdollah Allahverdi ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Angiotensin Converting Enzyme ◽  
Host Cells ◽  
Spike Protein ◽  
Potential Drug ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Approved Drugs ◽  
Fda Approved Drugs

Objective: The receptor-binding domain (RBD) of the S1 domain of the SARS-CoV- 2 Spike protein performs a key role in the interaction with Angiotensin-converting enzyme 2 (ACE2), leading to both subsequent S2 domain-mediated membrane fusion and incorporation of viral RNA in host cells. Methods: In this study, we investigated the inhibitor’s targeted compounds through existing human ACE2 drugs to use as a future viral invasion. 54 FDA approved drugs were selected to assess their binding affinity to the ACE2 receptor. The structurebased methods via computational ones have been used for virtual screening of the best drugs from the drug database. Key Findings: The ligands “Cinacalcet” and “Levomefolic acid” highaffinity scores can be a potential drug preventing Spike protein of SARS-CoV-2 and human ACE2 interaction. Levomefolic acid from vitamin B family was proved to be a potential drug as a spike protein inhibitor in previous clinical and computational studies. Besides that, in this study, the capability of Levomefolic acid to avoid ACE2 and Spike protein of SARS-CoV-2 interaction is indicated. Therefore, it is worth to consider this drug for more in vitro investigations as ACE2 and Spike protein inhibition candidate. Conclusion: The two Cinacalcet and Levomefolic acid are the two ligands that have highest energy binding for human ACE2 blocking among 54 FDA approved drugs.

DOCKING STUDY OF NOVEL N-SUBSTITUTED 2,5-BIS[(7-CHLOROQUINOLIN-4-YL)AMINO]PENTANOIC DERIVATIVES AS SELECTIVE HIGH-BINDER WITH ANGIOTENSIN CONVERTING ENZYME 2

INDIAN DRUGS ◽  
2020 ◽  
Vol 57 (08) ◽  
pp. 16-24
Author(s):  
Mohammed Oday Ezzat ◽  
Basma M. Abd Razik ◽  
Kutayba F. Dawood
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Active Site ◽  
Docking Study ◽  
World Health ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Pharmaceutical Properties ◽  
Novel Coronavirus

The prevalence of a novel coronavirus (2019-nCoV) in the last few months represents a serious threat as a world health emergency concern. Angiotensin-converting enzyme 2 (ACE2) is the host cellular receptor for the respiratory syndrome of coronavirus epidemic in 2019 (2019-nCoV). In this work, the active site of ACE2 is successfully located by Sitmap prediction tool and validated by different marketed drugs. To design and discover new medical countermeasure drugs, we evaluate a total of 184 molecules of 7-chloro-N-methylquinolin-4-amine derivatives for binding affinity inside the crystal structure of ACE2 located active site. A novel series of N-substituted 2,5-bis[(7-chloroquinolin-4-yl)amino]pentanoic acid derivatives is generated and evaluated for a prospect as a lead compound for (2019-nCoV) medication with a docking score range of (-10.60 to -8.99) kcal/mol for the highest twenty derivatives. Moreover, the ADME pharmaceutical properties were evaluated for further proposed experimental evaluation in vitro or in vivo

scholarly journals Uncontrolled mass use of hydroxychloroquine

2020 ◽  
Vol 11 (SPL1) ◽  
pp. 396-398
Author(s):  
Tugolbai Tagaev ◽  
Sagynali Mamatov ◽  
Farida Imanalieva ◽  
Vityala Yethindra ◽  
Altynai Zhumabekova ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Therapeutic Drug Monitoring ◽  
Severe Acute Respiratory Syndrome ◽  
Adverse Effects ◽  
Medical Advice ◽  
Therapeutic Drug ◽  
Converting Enzyme ◽  
Weak Base ◽  
Angiotensin Converting Enzyme 2

Hydroxychloroquine (HCQ) has previously been shown to inhibit coronavirus replication in vitro. But antiviral properties mechanisms are not well known, HCQ is a weak base that accumulates in lysosomes, modifies their pH, and interferes with some enzymes. In the lack of confirmed efficacy, the initial potential risk is not to expose patients to adverse effects. However, results from preliminary clinical studies have drawn inconclusive results regarding the efficacy of HCQ in coronavirus disease 2019 (COVID-19), due to several important weaknesses in research methodologies. Hypokalemia often occurs in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), possibly due to the particular tropism of SARS-CoV-2 with regard to Angiotensin-converting enzyme 2 (ACE2). The wide use of HCQ, even against medical advice, will show an impact on ongoing clinical trials. It is important that we can recruite COVID-19 patients in these research studies to generate appropriate data regarding drugs that show promising efficacy against COVID-19. Currently, only doctors should be allowed to prescribe HCQ, and treatment should be confined to hospital settings, with proper cardiac and therapeutic drug monitoring.

scholarly journals Drug Repurposing for Coronavirus (COVID-19): In Silico Screening of Known Drugs Against the SARS-CoV-2 Spike Protein Bound to Angiotensin Converting Enzyme 2 (ACE2) (6M0J)

2020 ◽  
Author(s):  
Konstantinos Kalamatianos
Keyword(s):  
Clinical Trials ◽  
Angiotensin Converting Enzyme ◽  
Experimental Validation ◽  
Antiviral Agents ◽  
Spike Protein ◽  
Binding Affinities ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Lead Compounds ◽  
Virtual Screening Approach

E2/21-12-2020<br><br>In this study FDA approved HCV antiviral drugs and their structural analogues – several of them in clinical trials - were tested for their inhibitory properties towards the SARS-CoV-2 Spike protein bound to angiotensin converting enzyme 2 (ACE2) (6M0J) using a virtual screening approach and computational chemistry methods. The most stable structures and the correspond-ing binding affinities of thirteen such antiretroviral com-pounds were obtained. Frontier molecular orbital theory, global reactivity descriptors, molecular docking calculations and electrostatic potential (ESP) analysis were used to hypothesize the bioactivity of these drugs against 6M0J. It is found that increased affinity for the protein is shown by inhibitors with large compound volume, relatively higher electrophilicity index, aromatic rings and heteroatoms that participate in hydrogen bonding. Amongst the drugs tested, four compounds 10-13 showed excellent results – binding affinities -11.2 to -11.5 kcal.mol-1. These four top scoring compounds may act as lead compounds for further experimental validation, clinical trials and even for the development of more potent antiviral agents against the SARS-CoV-2. <br><br><div><br></div><div>E1/24-08-2020</div><br>In this study FDA approved antiviral drugs and lopinavir analogues in clinical trials were tested for their inhibitory properties towards the SARS-CoV-2 Spike protein bound to<br>angiotensin converting enzyme 2 (ACE2) (6M0J) using a virtual screening approach and computational chemistry methods. Amongst the drugs tested, four compounds, PubChem CID 492005, CID 486507, CID 3010249 and<br><div>lopinavir showed excellent results – binding interactions -9.0 to -9.3 kcal.mol-1. These four top scoring compounds may act as lead compounds for further experimental validation, clinical trials and even for the development of more potent antiviral agents against the SARS-CoV-2.<br> </div><div><br></div>

scholarly journals An ACE2 Triple Decoy that neutralizes SARS-CoV-2 shows enhanced affinity for virus variants

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shiho Tanaka ◽  
Gard Nelson ◽  
C. Anders Olson ◽  
Oleksandr Buzko ◽  
Wendy Higashide ◽  
...  
Keyword(s):  
Md Simulation ◽  
Therapeutic Option ◽  
Receptor Binding Domain ◽  
Converting Enzyme ◽  
High Likelihood ◽  
Wild Type ◽  
Angiotensin Converting Enzyme 2 ◽  
High Affinity ◽  
Sustained Efficacy

AbstractThe SARS-CoV-2 variants replacing the first wave strain pose an increased threat by their potential ability to escape pre-existing humoral protection. An angiotensin converting enzyme 2 (ACE2) decoy that competes with endogenous ACE2 for binding of the SARS-CoV-2 spike receptor binding domain (S RBD) and inhibits infection may offer a therapeutic option with sustained efficacy against variants. Here, we used Molecular Dynamics (MD) simulation to predict ACE2 sequence substitutions that might increase its affinity for S RBD and screened candidate ACE2 decoys in vitro. The lead ACE2(T27Y/H34A)-IgG1FC fusion protein with enhanced S RBD affinity shows greater live SARS-CoV-2 virus neutralization capability than wild type ACE2. MD simulation was used to predict the effects of S RBD variant mutations on decoy affinity that was then confirmed by testing of an ACE2 Triple Decoy that included an additional enzyme activity-deactivating H374N substitution against mutated S RBD. The ACE2 Triple Decoy maintains high affinity for mutated S RBD, displays enhanced affinity for S RBD N501Y or L452R, and has the highest affinity for S RBD with both E484K and N501Y mutations, making it a viable therapeutic option for the prevention or treatment of SARS-CoV-2 infection with a high likelihood of efficacy against variants.

scholarly journals Drug Repurposing for Coronavirus (COVID-19): In Silico Screening of Known Drugs Against the SARS-CoV-2 Spike Protein Bound to Angiotensin Converting Enzyme 2 (ACE2) (6M0J)

2020 ◽  
Author(s):  
Konstantinos Kalamatianos
Keyword(s):  
Clinical Trials ◽  
Angiotensin Converting Enzyme ◽  
Experimental Validation ◽  
Antiviral Agents ◽  
Spike Protein ◽  
Binding Affinities ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Lead Compounds ◽  
Virtual Screening Approach

E2/21-12-2020<br><br>In this study FDA approved HCV antiviral drugs and their structural analogues – several of them in clinical trials - were tested for their inhibitory properties towards the SARS-CoV-2 Spike protein bound to angiotensin converting enzyme 2 (ACE2) (6M0J) using a virtual screening approach and computational chemistry methods. The most stable structures and the correspond-ing binding affinities of thirteen such antiretroviral com-pounds were obtained. Frontier molecular orbital theory, global reactivity descriptors, molecular docking calculations and electrostatic potential (ESP) analysis were used to hypothesize the bioactivity of these drugs against 6M0J. It is found that increased affinity for the protein is shown by inhibitors with large compound volume, relatively higher electrophilicity index, aromatic rings and heteroatoms that participate in hydrogen bonding. Amongst the drugs tested, four compounds 10-13 showed excellent results – binding affinities -11.2 to -11.5 kcal.mol-1. These four top scoring compounds may act as lead compounds for further experimental validation, clinical trials and even for the development of more potent antiviral agents against the SARS-CoV-2. <br><br><div><br></div><div>E1/24-08-2020</div><br>In this study FDA approved antiviral drugs and lopinavir analogues in clinical trials were tested for their inhibitory properties towards the SARS-CoV-2 Spike protein bound to<br>angiotensin converting enzyme 2 (ACE2) (6M0J) using a virtual screening approach and computational chemistry methods. Amongst the drugs tested, four compounds, PubChem CID 492005, CID 486507, CID 3010249 and<br><div>lopinavir showed excellent results – binding interactions -9.0 to -9.3 kcal.mol-1. These four top scoring compounds may act as lead compounds for further experimental validation, clinical trials and even for the development of more potent antiviral agents against the SARS-CoV-2.<br> </div><div><br></div>

scholarly journals Computational drug repurposing strategy predicted peptide-based drugs that can potentially inhibit the interaction of SARS-CoV-2 spike protein with its target (humanACE2)

PLoS ONE ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. e0245258
Author(s):  
Samuel Egieyeh ◽  
Elizabeth Egieyeh ◽  
Sarel Malan ◽  
Alan Christofells ◽  
Burtram Fielding
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Protein Interaction ◽  
Drug Repurposing ◽  
Spike Protein ◽  
Converting Enzyme ◽  
Peptide Drugs ◽  
Angiotensin Converting Enzyme 2 ◽  
Protein Protein Interaction ◽  
Potential Inhibitors

Drug repurposing for COVID-19 has several potential benefits including shorter development time, reduced costs and regulatory support for faster time to market for treatment that can alleviate the current pandemic. The current study used molecular docking, molecular dynamics and protein-protein interaction simulations to predict drugs from the Drug Bank that can bind to the SARS-CoV-2 spike protein interacting surface on the human angiotensin-converting enzyme 2 (hACE2) receptor. The study predicted a number of peptide-based drugs, including Sar9 Met (O2)11-Substance P and BV2, that might bind sufficiently to the hACE2 receptor to modulate the protein-protein interaction required for infection by the SARS-CoV-2 virus. Such drugs could be validated in vitro or in vivo as potential inhibitors of the interaction of SARS-CoV-2 spike protein with the human angiotensin-converting enzyme 2 (hACE2) in the airway. Exploration of the proposed and current pharmacological indications of the peptide drugs predicted as potential inhibitors of the interaction between the spike protein and hACE2 receptor revealed that some of the predicted peptide drugs have been investigated for the treatment of acute respiratory distress syndrome (ARDS), viral infection, inflammation and angioedema, and to stimulate the immune system, and potentiate antiviral agents against influenza virus. Furthermore, these predicted drug hits may be used as a basis to design new peptide or peptidomimetic drugs with better affinity and specificity for the hACE2 receptor that may prevent interaction between SARS-CoV-2 spike protein and hACE2 that is prerequisite to the infection by the SARS-CoV-2 virus.

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